Late Phase Administration Anakinra as a Rescue Treatment for Inhaled Allergen Challenge-Induced Airway Inflammation

NCT03513458 | Withdrawn Phase 1 DMC FDA Drug

• 2 other identifiers: 17-07791R01HL135235-01A1
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

Purpose: The primary objective of this study is to examine the effectiveness of anakinra as a rescue treatment for allergic airway inflammation. Utilizing an inhaled allergen challenge model, the investigators will determine the effectiveness of a single 1 mg/kg dose of anakinra administered after inhaled allergen challenge for mitigating features of airway inflammation. Participants: 25 mild allergic asthmatics sensitized to Dermatophagoides farinae (D. farinae) Procedures (methods): 12 eligible subjects of 25 volunteers will participate in a double blind cross-over study. Following randomization to the placebo or anakinra treatment group, subjects will undergo inhalation of D. farinae, and their early and late phase asthmatic responses will be measured. Subjects will undergo induced sputum sampling, methacholine challenge, and mucociliary clearance measures. After completion of period 1, subjects will cross over to the alternate study arm.

Conditions

Asthma

Keywords

Late Phase Asthmatic Response; Allergen Challenge

Outcome Measures

Primary Outcomes (1)

• Maximum % FEV1 drop from Baseline during LPR period

  The principal endpoint will be maximal % drop in Forced Expiratory Volume in 1 second (FEV1) from baseline during the LPR period (3-10 hours). The FEV1 following saline and prior to the first dose of antigen during the inhaled allergen challenge will be considered the baseline value. Declines in FEV1 will be measured as a % drop from the baseline. A provocative dose causing a 20% fall FEV1 (PD20) is determined during the allergen challenge.

  Baseline and 3-10 hours following PD20

Secondary Outcomes (11)

• Area under the curve (AUC) measuring % drop in FEV1 in the LPR

  Baseline and 3-10 hours following PD20

• Change in Methacholine reactivity, as measured by the concentration of methacholine resulting in a 20% drop in FEV1 (PC20)

  Baseline and 24 hours post allergen challenge

• Fractional exhaled Nitric Oxide (FeNO) as an exploratory biomarker

  Baseline and 24 hours post allergen challenge

• Change in % eosinophils in induced sputum

  Baseline and 24 hours post allergen challenge

• Change in % neutrophils in induced sputum

  Baseline and 24 hours post allergen challenge

Study Arms (2)

Anakinra then Placebo

EXPERIMENTAL

Subjects randomized to this arm will receive the experimental treatment of Anakinra on their first exposure to Dermatophagoides Farinae (dust mite) allergen challenge, followed by the Anakinra matching placebo on their second exposure.

Biological: Anakinra; Other: Anakinra Matching Placebo; Drug: Dermatophagoides Farinae

Placebo then Anakinra

EXPERIMENTAL

Subjects randomized to this arm will receive the inactive placebo on their first exposure to the Dust Mite Allergen challenge, followed by the experimental treatment of Anakinra on their second exposure.

Biological: Anakinra; Other: Anakinra Matching Placebo; Drug: Dermatophagoides Farinae

Interventions

Anakinra BIOLOGICAL

A single 1mg/kg subcutaneous injection (up to 100 mg) of Anakinra will be administered at the onset of the LPR, roughly three hours post allergen challenge, to model Anakinra use in an emergency care setting.

Also known as: Kinaret

Anakinra then Placebo; Placebo then Anakinra

Anakinra Matching Placebo OTHER

A single dose of matching placebo will be administered at the onset of the LPR, roughly three hours post allergen challenge, to model Anakinra use in an emergency care setting.

Also known as: dummy

Anakinra then Placebo; Placebo then Anakinra

Dermatophagoides Farinae DRUG

Standardized house dust mite Dermatophagoides farinae (D. farinae) allergen extract at 30,000 allergen units (AU)/mL for inhalation (provided by Greer Laboratories, Lenoir, NC).

Also known as: Allergen extract

Anakinra then Placebo; Placebo then Anakinra

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Age range 18-45 years, inclusive
• FEV1 of at least 80% of predicted and FEV1/FVC (forced vital capacity) ratio of at least 0.7 (without use of bronchodilator medications for 12 hours or long acting beta agonists for 24 hours), consistent with lung function of persons with no more than mild episodic or mild persistent asthma.
• Physician diagnosis of asthma
• Positive methacholine inhalation challenge as performed in the separate screening protocol within the prior 12 months (defined as provocative concentration of methacholine of 10 mg/mL or less producing a 20% fall in FEV1 (PC20 methacholine)
• Allergic sensitization to house dust mite (D. farinae) as confirmed by positive immediate skin prick test response
• Clinical reactivity to D. farinae assessed through inhaled allergen challenge with a decline in FEV1 of ≥20% from baseline in the early asthmatic response and ≥15% in the late asthmatic response.
• Negative pregnancy test for females who are not s/p hysterectomy with oophorectomy or who have not been amenorrheic for 12 months or more.
• Oxygen saturation of \>94% and blood pressure within the following limits: (Systolic between 150-90 mmHg, Diastolic between 90-60 mmHg).
• Ability to provide an induced sputum sample.
• Negative intracutaneous tuberculin skin test (PPD) defined as less than 5mm induration for the purpose of this protocol (positive PPD contraindication to anakinra injection). A negative tuberculosis (TB) test within the past year (either PPD or quantiferon TB Gold) is also acceptable

You may not qualify if:

• Clinical contraindications:
• Any chronic medical condition considered by the PI as a contraindication to participation in the study including significant cardiovascular disease, diabetes, chronic renal disease, chronic thyroid disease, history of chronic infections or immunodeficiency.
• Pregnancy or nursing a baby
• History of latex allergy/sensitivity
• Allergy/sensitivity to anakinra or its formulation
• Physician directed emergency treatment for an asthma exacerbation within the preceding 12 months.
• Exacerbation of asthma more than 2x/week which could be characteristics of a person of moderate or severe persistent asthma as outlined in the current NHLBI guidelines for diagnosis and management of asthma.
• Daily requirements for albuterol due to asthma symptoms (cough, wheeze, chest tightness) which would be characteristic of a person of moderate or severe persistent asthma as outlined in the current NHLBI guidelines for diagnosis and management of asthma (not to include prophylactic use of albuterol prior to exercise).
• Viral upper respiratory tract infection within 4 weeks of challenge.
• Any acute infection requiring antibiotics within 4 weeks of exposure or fever of unknown origin within 4 weeks of challenge.
• Severe asthma
• Mental illness of history of drug or alcohol abuse that, in the opinion of the investigator, would interfere with the participant's ability to comply with study requirements.
• Cigarette smoking \>1 pack per month
• Nighttime symptoms of cough or wheeze greater than 1x/week at baseline (not during a clearly recognized viral induced asthma exacerbation) which would be characteristic of a person of moderate or severe persistent asthma as outlined in the current NHLBI guidelines for diagnosis and management of asthma.
• Allergy/sensitivity to study drugs or their formulations

Sponsors & Collaborators

• University of North Carolina, Chapel Hill: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

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MeSH Terms

Conditions

Asthma

Interventions

Interleukin 1 Receptor Antagonist Protein; Receptors, Interleukin-6; Antigens, Dermatophagoides; Allergens

Condition Hierarchy (Ancestors)

Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases

Intervention Hierarchy (Ancestors)

Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Receptors, Interleukin; Receptors, Cytokine; Receptors, Immunologic; Receptors, Cell Surface; Membrane Proteins; Antigens

Study Officials

• Michelle Hernandez, MD

  University of North Carolina, Chapel Hill

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: The randomization to study arms will be done by the department biostatistician and communicated to Investigational Drug Services to maintain the double-blind nature of the study.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Subjects are randomized to one of two arms, either taking Anakinra or placebo. After a washout period, the subjects will be moved to the opposite arm.

Study Record Dates

• First Submitted: April 19, 2018
• First Posted: May 1, 2018
• Study Start: September 1, 2020
• Primary Completion: December 1, 2021
• Study Completion: December 1, 2021
• Last Updated: May 14, 2021

Record last verified: 2021-05

Data Sharing

• IPD Sharing: Will not share